C-(2-phenyl-cyclohexyl)-methylamine compounds for the treatment of anxiety disorders

ABSTRACT

Pharmaceutical formulations of [2-(3-methoxyphenyl)-cyclohexylmethyl]-dimethylamine and the metabolites thereof for treating anxiety, anxiety attacks and disorders as well as depression. Related methods of treating anxiety and anxiety attacks or depression are also provided, including methods of administering the active compounds as adjuvants to an antidepressant.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International patent applicationSer. No. PCT/EP2004/013439 filed Nov. 26, 2004, which claims priority toGerman patent application Serial No. 103 56 362.8 filed Nov. 28, 2003,the disclosures of which are incorporated herein in their entireties.

FIELD OF THE INVENTION

Pharmaceutical formulations of[2-(3-methoxyphenyl)-cyclohexylmethyl]-dimethylamine and the metabolitesthereof for treating anxiety, anxiety attacks and disorders as well asdepression. Related methods of treating anxiety and anxiety attacks ordepression are also provided, including methods of administering theactive compound(s) as adjuvant(s) to at least one antidepressant.

BACKGROUND OF THE INVENTION

Anxiety disorders are illnesses of which the main symptoms aremanifestations of unrealistic or excessively pronounced anxiety. In thecase of phobias, to the sub-types of which so-called simple phobias,social anxiety disorders and agoraphobias belong, the anxiety attacksare associated with particular objects or situations. However,pronounced anxiety attacks can also occur without being triggered byspecific situations or circumstances. Thus panic disorders aredistinguished by recurring, pronounced anxiety attacks which are notforeseeable and therefore lead to anticipatory anxiety. Generalizedanxiety disorders are floating, lasting anxieties with diverse, inparticular vegetative symptoms. Patients who suffer from posttraumaticstress disorders (PTSD) were exposed to a brief or long-lasting event oroccurrence of exceptional threat or with catastrophic proportions. Thisevent would induce a deep-seated despair in virtually anyone. Thoseaffected live through the stresses again and again in quick-fire images,accompanied by psychovegetative symptoms, such as, inter alia, severeoutbreaks of perspiration and a racing heart. Obsessive compulsivedisorders (OCD) are characterized by recurring unpleasant thoughts,impulses or actions which last several weeks, are experienced as beingpart of the self and against which at least partial resistance is givensince the person affected finds them senseless. Mixed anxiety disordersor anxiety disorders accompanied with depressions very often exist.

Depressions are affectivity disorders in which a depressive syndrome isof prime significance, depressive meaning associated with depression orof sad mood. The depressive illnesses include unipolar severedepressions with or without delusion, moderate depressions, milddepressions, dysthymia, melancholy, bipolar depressions (bipolar illnessI, mania and severe depression; bipolar illness II, hypomania and severedepressions; cyclothymic personality disorders, hypomania and milddepressions).

Those pharmaceutical formulations with an anxiolytic and antidepressantaction based on an inhibition of the reuptake of the monoaminesnoradrenaline and/or serotonin are widely used for therapy of anxietydisorders and depressions (Pacher, P., Kohegyi, E., Kecskemeti, V.,Furst, S., Current Medicinal Chemistry 2001, 8, 89-100; Goddard, A. W.,Coplan, J. D. Gorman, J. M., Charney, D. S., in: Neurobiology of mentalillness, Charney, D. S., Nestler, E. J., Bunney, B. S. (eds.), OxfordUniversity Press, New York, 1999, p. 548-563). A great disadvantage inthis context is that the monoamine reuptake inhibitors display theiranxiolytic and antidepressant action only after several weeks oftreatment and achieve their full activity only after approx. 3-4 weeks.At the start of treatment of patients suffering from anxiety, and alsothose suffering from depression, standard medications frequentlyintensify or induce anxiety states, unrest, increased irritability andthoughts of suicide. These psychomotor states of excitation and thoughtsof suicide occur particularly frequently in the first days after thestart of therapy both with tricyclic antidepressants, selectiveserotonin reuptake inhibitors (so-called SSRIs) and with mixedserotonin-noradrenalin reuptake inhibitors, and are associated with anincreased risk of suicide (Jick, H., Kaye, J. A., Jick, S. S.:Antidepressants and the risk of suicidal behaviours, JAMA (2004) 292,338-343). This results in the need for strict monitoring of patientsbeing treated with standard antidepressants, and possibly for areduction in the dose. For anxiety disorders and depressions there istherefore a great need for a therapy which is distinguished by an earlyonset of action and causes no anxiogenic side effects and therefore noincreased risk of suicide at the start of therapy, or inhibits thoseinduced by antidepressants.

Since approx. 20-30% of patients suffering from anxiety disorders anddepressions show no improvement after treatment with approvedantidepressants and anxiolytics, new therapeutic systems for treatmentof hitherto pharmacotherapy-resistant patients are of high benefit.

The monoamine reuptake inhibitors used for therapy of anxiety disordersand depressions are also used for treatment of chronic pain patients. Inaddition to the actual antidepressant and anxiolytic actions, reuptakeinhibitors of noradrenaline and serotonin lead to an independentanalgesic action in that descending pain inhibition pathways at thelevel of the spinal marrow are activated. Monoamine reuptake inhibitorsare employed clinically for monotherapy of neuropathic pain, and also asan adjuvant to opiates for treatment of chronic pain (inter aliainflammatory pain, tumour pain, fibromyalgia) (Sindrup, in: Yaksh, T.L., et al., Anesthesia. Biological foundations. Philadelphia:Lippincott-Raven, 1997, 987-997). Since chronic pain is accompanied byanxiety disorders or depressions in a large number of patients, asubstance with μ-opiate agonistic properties combined with a clinicallyrelevant serotonin and/or noradrenaline reuptake inhibition isparticularly favourable.

SUMMARY OF THE INVENTION

One object of the present invention is to provide substances, inparticular opioid substance, which are suitable for therapy of anxietydisorders, depressions or mixed forms of anxiety and depression with orwithout chronic pain. In particular, the invention provides compoundswith an earlier onset of action compared with the monoamine reuptakeinhibitors widely used for anxiety disorders and depressions.

It has now been found, surprisingly, that2-(3-methoxyphenyl)-cyclohexylmethyl)-dimethylamine and also itsmetabolites, and in this context in particular3-(2-dimethylaminomethyl-cyclohexyl)-phenol, have a therapeuticallyrelevant anxiolytic and antidepressant action component which isdistinguished by an early onset of action and the absence of anxiogeniceffects. Mechanistic investigations show the content of the μ-opiateagonistic component in the anxiolytic as well as in the antidepressantaction and in particular in the early onset of action. The substanceshave pronounced anxiolytic, antidepressant and analgesic actions and aretherefore suitable for treatment of depressions, anxiety disorders andpain. On the basis of the potentiation, induced by the μ-opiateagonistic action component, of the anxiolytic and antidepressant actionsmediated by serotonin and noradrenaline reuptake inhibition, the useaccording to the invention of the compounds mentioned is a particularlyeffective treatment possibility precisely also for pharmaco-resistantanxiety and depression patients.

The invention accordingly provides the use of

3-(2-dimethylaminomethyl-cyclohexyl)-phenol,

(1R, 2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol,

[2-(3-methoxyphenyl)-cyclohexylmethyl]-dimethylamine,

(1R, 2R)-[2-(3-methoxyphenyl)-cyclohexylmethyl]-dimethylamine,

sulfuric acid mono-[3-(2-dimethylaminomethyl-cyclohexyl)-phenyl]ester,

sulfuric acid mono-(1R,2R)-[3-(2-dimethylaminomethyl-cyclohexyl)-phenyl]ester,

3-(2-methylaminomethyl-cyclohexyl)-phenol,

(1R, 2R)-3-(2-methylaminomethyl-cyclohexyl)-phenol,

3-(2-dimethylaminomethyl-cyclohexyl)-phenol, N-oxide,

(1R, 2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol, N-oxide,

6-[3-(2-dimethylaminomethyl-cyclohexyl)-phenoxy]-3,4,5-trihydroxy-tetrahydropyran-2-carboxylicacid,

6-[(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenoxy]-3,4,5-trihydroxy-tetrahydropyran-2-carboxylicacid,

4-(2-dimethylaminomethyl-cyclohexyl)-catechol,

(1R,2R)-4-(2-dimethylaminomethyl-cyclohexyl)-catechol,

3-(2-aminomethyl-cyclohexyl)-phenol,

(1R,2R)-3-(2-aminomethyl-cyclohexyl)-phenol,

C-[2-(3-methoxy-phenyl)-cyclohexyl]-methylamine,

(1R,2R)-C-[2-(3-methoxy-phenyl)-cyclohexyl]-methylamine,

[2-(3-methoxy-phenyl)-cyclohexylmethyl]-methylamine,

(1R,2R)-[2-(3-methoxy-phenyl)-cyclohexylmethyl]-methylamine,

[2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethylamine, N-oxide or

(1R,2R)-[2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethylamine, N-oxide,

optionally in the form of their racemates, their pure stereoisomers, inparticular enantiomers or diastereomers, or in the form of mixtures ofthe stereoisomers, in particular the enantiomers or diastereomers, inany desired mixture ratio; in the form shown or in the form of theiracids or their bases or in the form of their salts, in particular thephysiologically acceptable salts, or in the form of their solvates, inparticular the hydrates;

for the preparation of a pharmaceutical formulation for treatment ofanxiety states or for the preparation of an adjuvant to standardantidepressants as well as for related methods of treatment.

It is particularly preferable in this context if the compounds used arein the form of 1R,2R enantiomers.

The term salt is to be understood as meaning any form of the activecompound according to the invention in which this assumes an ionic formor is charged and is coupled with a counter-ion (a cation or anion) oris in solution. This is also to be understood as meaning complexes ofthe active compound with other molecules and ions, in particularcomplexes which are complexed via ionic interactions. In particular,this is understood as meaning (and this is also a preferred embodimentof this invention) physiologically acceptable salts, in particularphysiologically acceptable salts with cations or bases andphysiologically acceptable salts with anions or acids or also a saltformed with a physiologically acceptable acid or a physiologicallyacceptable cation.

The preferred salt of the compounds used is the hydrochloride.

Physiologically acceptable is to be understood as meaning that thesubstance, in particular the salt as such, is acceptable when used onhumans or mammals, that is to say, for example, does not have anon-physiological (e.g. toxic) action.

In the context of this invention, the term physiologically acceptablesalt with anions or acids is understood as meaning salts of at least oneof the compounds according to the invention—usually protonated, forexample on the nitrogen—as the cation with at least one anion which isphysiologically acceptable—in particular when used on humans and/ormammals. In particular, in the context of this invention this isunderstood as meaning the salt formed with a physiologically acceptableacid, namely salts of the particular active compound with inorganic ororganic acids which are physiologically acceptable—in particular whenused on humans and/or mammals. Examples of physiologically acceptablesalts of particular acids are salts of: hydrochloric acid, hydrobromicacid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid,oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid,fumaric acid, lactic acid, citric acid, glutamic acid,1,1-dioxo-1,2-dihydro-1λ⁶-benzo[d]isothiazol-3-one (saccharin),monomethylsebacic acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinicacid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid,α-liponic acid, acetylglycine, acetylsalicylic acid, hippuric acidand/or aspartic acid. The hydrochloride salt is particularly preferred.

In the context of this invention, the term salt formed with aphysiologically acceptable acid is understood as meaning salts of theparticular active compound with inorganic or organic acids which arephysiologically acceptable - in particular when used on humans and/ormammals. The hydrochloride is particularly preferred. Examples ofphysiologically acceptable acids are: hydrochloric acid, hydrobromicacid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid,oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid,lactic acid, citric acid, glutamic acid,1,1-dioxo-1,2-dihydro-1λ⁶-benzo[d]isothiazol-3-one (saccharin),monomethylsebacic acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinicacid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid,α-liponic acid, acetylglycine, acetylsalicylic acid, hippuric acidand/or aspartic acid.

In the context of this invention, the term physiologically acceptablesalt with cations or bases is understood as meaning at least one of thecompounds according to the invention—usually a (deprotonated) acid—asthe anion with at least one, preferably inorganic cation, which arephysiologically acceptable—in particular when used on humans and/ormammals. Particularly preferred salts are the salts of the alkali metalsand alkaline earth metals, but also with NH₄+, in particular (mono)- or(di)sodium, (mono)- or (di)potassium, magnesium or calcium salts.

In the context of this invention, the term salt formed with aphysiologically acceptable cation is understood as meaning salts of atleast one of the particular compounds as the anion with at least oneinorganic cation which is physiologically acceptable—in particular whenused on humans and/or mammals. Particularly preferred salts are thesalts of the alkali metals and alkaline earth metals, but also NH₄+, inparticular (mono)- or (di)sodium, (mono)- or (di)potassium, magnesium orcalcium salts.

The present invention also provides a method for treatment of anxietydisorders in a mammal and/or human, in which a therapeutically activeamount of a compound used according to the invention is administered.

In this context, it is of advantage to administer this compound at thefirst occurrence of anxiety disorders, since they show an early onset ofaction.

The present invention also provides a method for treatment of anxietydisorders or depressions, in which a compound used according to theinvention is administered as an adjuvant to standard antidepressants, inorder to inhibit the psychomotor states of excitation induced by theantidepressants at the start of therapy and the increased risk ofsuicide. In the context of this invention, standard antidepressants areunderstood as meaning all the approved antidepressants.

According to the present investigations, the substances used, and inparticular (1R,2R)-3-(2-diethylaminomethyl-cyclohexyl)-phenol, arepotent anxiolytics, antidepressants and analgesics, that is to say havean additional and clinically relevant anxiolytic action component.

The compounds used according to the invention can moreover also beemployed for the preparation of a pharmaceutical formulation fortreatment of obsessive compulsive disorders, migraine, fibromyalgia,eating disorders, bulimia, hyperactivity, drug dependency, addiction andwithdrawal, trichotillomania, Tourette's syndrome, skin diseases, inparticular postherapeutic neuralgia and pruritus, psychoses, impairedmemory, cognitive disorders and/or Alzheimer's disease.

Suitable additives and/or auxiliary substances to the compounds usedaccording to the invention in the process for the preparation of thepharmaceutical formulation are all the substances known to the expertfrom the prior art for achieving galenical formulations. The choice ofthese auxiliary substances and the amounts thereof to be employed dependon whether the pharmaceutical formulation is to be administered orally,intravenously, intraperitoneally, intradermally, intramuscularly,intranasally, buccally or locally. Formulations in the form of tablets,chewable tablets, coated tablets, capsules, granules, drops, juices orsyrups are suitable for oral administration, and solutions, suspensions,easily reconstitutable dry formulations and sprays are suitable forparenteral, topical and inhalatory administration. Suppositories for usein the rectum are a further possibility. The use in a depot in dissolvedform, a carrier film or a patch, optionally with the addition of agentswhich promote penetration through the skin, are examples of suitableforms for percutaneous administration. Examples of auxiliary substancesand additives for the oral administration forms are disintegratingagents, lubricants, binders, fillers, mould release agents, optionallysolvents, flavourings, sugars, in particular carrier agents, diluents,dyestuffs, antioxidants etc. For suppositories, inter alia, waxes andfatty acid esters can be used, and for parenteral administrationcompositions carrier substances, preservatives, suspension auxiliariesetc. can be used. The amounts of active compound to be administered topatients vary as a function of the weight of the patient, the mode ofadministration and the severity of the disease. The compounds usedaccording to the invention can be released in a delayed manner fromformulation forms which can be used orally, rectally or percutaneously.Corresponding sustained-release formulations, in particular in the formof a “once daily” preparation which has to be taken only once a day, areparticularly preferred for the indication according to the invention.

Pharmaceutical formulations which comprise at least 0.05 to 90.0% of theactive compound, in particular low active dosages, in order to avoidside effects or analgesic actions, are preferred. 0.1 to 5,000 mg/kg, inparticular 1 to 500 mg/kg, preferably 2 to 250 mg/kg of body weight of aleast one compound used according to the invention are conventionallyadministered. However, the administration of 0.01- 5 mg/kg, preferably0.03 to 2 mg/kg, in particular 0.05 to 1 mg/kg, is also preferred andconventional.

Auxiliary substances can be, for example: water, ethanol, 2-propanol,glycerol, ethylene glycol, propylene glycol, polyethylene glycol,polypropylene glycol, glucose, fructose, lactose, sucrose, dextrose,molasses, starch, modified starch, gelatine, sorbitol, inositol,mannitol, microcrystalline cellulose, methylcellulose,carboxymethylcellulose, cellulose acetate, shellac, cetyl alcohol,polyvinylpyrrolidone, paraffins, waxes, naturally occurring andsynthetic gums, gum acacia, alginates, dextran, saturated andunsaturated fatty acids, stearic acid, magnesium stearate, zincstearate, glyceryl stearate, sodium lauryl sulfate, edible oils, sesameoil, coconut oil, groundnut oil, soya bean oil, lecithin, sodiumlactate, polyoxyethylene and -propylene fatty acid esters, sorbitanfatty acid esters, sorbic acid, benzoic acid, citric acid, ascorbicacid, tannic acid, sodium chloride, potassium chloride, magnesiumchloride, calcium chloride, magnesium oxide, zinc oxide, silicondioxide, titanium oxide, titanium dioxide, magnesium sulfate, zincsulfate, calcium sulfate, potash, calcium phosphate, dicalciumphosphate, potassium bromide, potassium iodide, talc, kaolin, pectin,crospovidone, agar and bentonite.

The pharmaceutical formulations and pharmaceutical compositions areprepared with the aid of means, devices, methods and processes which arewell-known in the prior art of pharmaceutical formulation, such as aredescribed, for example, in “Remington's Pharmaceutical Sciences”, ed. A.R. Gennaro, 17th ed., Mack Publishing Company, Easton, Pa. (1985), inparticular in part 8, chapter 76 to 93.

Thus e.g. for a solid formulation, such as a tablet, the active compoundof the pharmaceutical formulation, i.e. a compound of[2-(3-methoxyphenyl)-cyclohexylmethyl]-dimethylamine, its metabolites orone of the pharmaceutically acceptable salts, can be granulated with apharmaceutical carrier, e.g. conventional tablet constituents, such asmaize starch, lactose, sucrose, sorbitol, talc, magnesium stearate,dicalcium phosphate or pharmaceutically acceptable gums, andpharmaceutical diluents, such as e.g. water, in order to form a solidcomposition which comprises a compound according to the invention or apharmaceutically acceptable salt thereof in homogeneous distribution.Homogeneous distribution is understood here as meaning that the activecompound is uniformly distributed over the entire composition, so thatthis can easily be divided into unit dose forms, such as tablets, pillsor capsules, having the same activity. The solid composition is thendivided into unit dose forms. The tablets or pills of the pharmaceuticalformulation according to the invention or of the compositions accordingto the invention can also be coated or compounded in another manner inorder to provide a dose form with delayed release. Suitable coatingcompositions are, inter alia, polymeric acids and mixtures of polymericacids with materials such as e.g. shellac, cetyl alcohol and/orcellulose acetate.

Although the pharmaceutical formulations show only few side effects, itmay be of advantage—should this be necessary at all—for example to avoidcertain forms of dependency, also to use morphine antagonists, inparticular naloxone, naltrexone and/or levallorphan, in addition to thecompounds used.

2-(3-Methoxyphenyl)-cyclohexylmethyl]-dimethylamine and(1R,2R)-[2-(3-methoxyphenyl)-cyclohexylmethyl]-dimethylamine and theirpreparation are known from DE 195 25 137 A1 example 8 and U.S. Pat. No.5,733,936 example 8, where the absolute stereochemistry of the compound(-6) prepared according to example 8 is certainly correctly (1R,2R) andnot (1R,2S. 3-(2-Dimethylaminomethyl-cyclohexyl) -phenol and(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol and theirpreparation are also known from DE 195 25 137 A1 example 10 and U.S.Pat. No. 5,733,936 example 10, where the absolute stereochemistry of thecompound (-7) prepared according to example 10 is certainly correctly(1R,2R) and not (1R,2S).

The compounds and their preparation which are not yet known from DE 19525 137 A1 or U.S. Pat. No. 5,733,936 were prepared in accordance withthe examples.

Certain embodiments of the present invention may be further understoodby reference to the following specific examples. These examples and theterminology used herein are for the purpose of describing particularembodiments only and are not intended to be limiting.

EXAMPLES

Generally, the purification and enantiomer separation in all theprocesses mentioned as an example are carried out at the various stagesby column chromatography or, predominantly, HPLC, where appropriate onchiral stationary phases.

Example 1 Preparation of(1R,2R)-[2-(3-methoxyphenyl)-cyclohexylmethyl]-methylamine hydrochloride

[2-(3-Methoxyphenyl)-cyclohexylmethyl]-methylamine and(1R,2R)-[2-(3-methoxyphenyl)-cyclohexylmethyl]-methylamine, inparticular the hydrochloride salt thereof, are prepared as follows:

3.16 ml (25.2 mmol) phenyl chloroformate were added dropwise to asolution of 5.67 g (22.9 mmol)(1R,2R)-[2-(3-methoxyphenyl)-cyclohexylmethyl]-dimethylamine in 390 mldry toluene at the boiling point. After the mixture had been heatedunder reflux for three hours, it was cooled to 20° C., and washedsuccessively with 100 ml each of sodium hydroxide solution (2.5N),distilled water, hydrochloric acid (1N) and a saturated sodium chloridesolution. It was dried over sodium sulfate and evaporated in vacuo. Theresidue was taken up in 192.5 ml ethylene glycol and 46 ml sodiumhydroxide solution (5N) and the mixture was stirred at 110° C. for atotal of 8 hours, it being topped up twice with 10 ml sodium hydroxidesolution (5N) each time. After cooling, it was diluted with 100 mldistilled water and extracted three times with 50 ml methylene chlorideeach time. The extracts were washed with distilled water and a saturatedsodium chloride solution, dried over sodium sulfate and evaporated invacuo and the residue was dried. The residue (5.03 g) was dissolved in32.3 ml 2-butanone, 2.7 ml trimethylchlorosilane were added to thesolution and the mixture was stirred for 15 minutes. 100 ml dry diethylether were then added, the mixture was stirred at 20° C. for a further 2hours and the solid was filtered off with suction. It was washedthoroughly with diethyl ether and dried in vacuo. By this procedure,3.56 g (57.6 % of theory) of the title compound were obtained in theform of colourless crystals which melted at 165-167° C.

Example 2 Preparation of(1R,2R)-3-(2-methylaminomethyl-cyclohexyl)-phenol hydrochloride

3.55 g (15.2 mmol) of the product from example 1 were stirred underreflux in 4.59 ml hydrobromic acid (47-48% HBr) for 7.5 h. Aftercooling, ice/water was added and the mixture was then rendered alkalinewith sodium hydroxide solution (6N). It was extracted three times with50 ml ethyl acetate each time. The extracts were washed with a saturatedsodium chloride solution, dried over sodium sulfate and evaporated invacuo. The residue (2.91 g) was dissolved in 16.4 ml 2-butanone andconverted into the hydrochloride with 1.63 ml trimethylchlorosilane asdescribed under example 1. By this procedure, 2.98 g (76.5% of theory)of the title compound were obtained as a slightly yellow-coloured solidwhich melted at 173-175° C.

Example 3 Preparation of sulfuric acidmono-(1R,2R)-[3-(2-dimethylaminomethyl-cyclohexyl)-phenyl] ester

Sulfuric acid mono-[3-(2-dimethylaminomethyl-cyclohexyl)-phenyl] esteror sulfuric acidmono-(1R,2R)-[3-(2-dimethylaminomethyl-cyclohexyl)-phenyl] ester wasprepared as follows:

15.9 g (4.70 mmol) of a 2.9 % strength solution of sulfuric acid indimethylformamide were added dropwise to a solution of 1.00 g (3.92mmol) (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol; hydrochlorideand 0.94 g (4.70 mmol) dicyclohexylcarbodiimide in 20 mldimethylformamide at 0° C., while stirring. When the addition had ended,the mixture was stirred further for another 10 minutes and a pH of 9 wasthen established with dilute ammonium hydroxide solution. Theprecipitate formed was separated off, washed with ethyl acetate anddried in vacuo. 0.26 g (21% of theory) of the title compound wasobtained in this way as a white solid.

Example 4 Preparation of6-[(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenoxy]-3,4,5-trihydroxy-tetrahydropyran-2-carboxylicacid

6-[3-(2-Dimethylaminomethyl-cyclohexyl)-phenoxy]-3,4,5-trihydroxy-tetrahydropyran-2-carboxylicacid and6-[(1R,2R)-3-(2-Dimethylaminomethyl-cyclohexyl)-phenoxy]-3,4,5-trihydroxy-tetrahydropyran-2-carboxylicacid were prepared as follows:

A mixture of 2.33 g (10 mmol)(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol, 3.58 g (9 mmol)acetobromo-α-D-glucuronic acid methyl ester and 0.23 g (9.5 mmol)lithium hydroxide in 23 ml dry methanol was first stirred at 20° C. for30 minutes, a solution of 0.65 g lithium hydroxide in 25 ml water wasthen added and the mixture was stirred again for 30 minutes. It wasextracted with ethyl acetate and the aqueous phase was adjusted to a pHof 3.5 by addition of acetic acid and extracted again with ethylacetate. The aqueous phase was evaporated in vacuo and the residue waspurified by HPLC. 0.85 g (23% of theory) of the title compound wasobtained in this manner in the form of a white powder.

Example 5 Preparation of(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol, N-oxide

3-(2-Dimethylaminomethyl-cyclohexyl)-phenol, N-oxide and(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol, N-oxide wereprepared as follows:

10.5 ml hydrogen peroxide were added to a solution of 5.60 g (24 mmol)(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol in 28 ml methanoland the mixture was stirred first at 50° C. for 3 hours and then at 20°C. for 15 hours. After addition of 3.30 g potassium carbonate, themixture was stirred again for 3 hours, the solid was then filtered offand the filtrate was evaporated in vacuo. The residue was taken up in 30ml ethanol. Solid constituents were separated off by filtration, thefiltrate was evaporated in vacuo and the residue was dried. 5.50 g (80%of theory) of the title compound were obtained in this way in the formof an oil which gradually solidified.

Example 6 Preparation of[2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethylamine, N-oxide

[2-(3-Methoxy-phenyl)-cyclohexylmethyl]-dimethylamine, N-oxide and(1R,2R)-[2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethylamine, N-oxidewere prepared by the procedure in example 5 using corresponding startingsubstances.

Example 7 Preparation of 4-(2-dimethylaminomethyl-cyclohexyl)-catechol

The preparation of 4-(2-dimethylaminomethyl-cyclohexyl)-catechol wascarried out in accordance with the following reaction equation(stereochemistry not taken into consideration):

In this equation, Method 1 BuLi moreover means the synthesis, well-knownto the expert, via bromine-lithium exchange with BuLi reagents andMethod 2 Grignard means the synthesis, well-known to the expert, via Mgreagents.

Example 8 Preparation of C-[2-(3-methoxy-phenyl)-cyclohexyl]-methylamine

The preparation of C-[2-(3-methoxy-phenyl)-cyclohexyl]-methylamine wascarried out in accordance with the following reaction equation(stereochemistry not taken into consideration; Bn represents the benzylradical):

Example 9 Preparation of (1R,2R)-3-(2-aminomethyl-cyclohexyl)-phenol

The preparation of 3-(2-aminomethyl-cyclohexyl)-phenol or(1R,2R)-3-(2-aminomethyl-cyclohexyl)-phenol was carried out inaccordance with the following reaction equation:

Example 10 In Vitro Isolation of the Metabolites

[2-(3-Methoxyphenyl)-cyclohexylmethyl]-dimethylamine hydrochloride andin another example (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenolhydrochloride was dissolved in TRIS/HCl buffer pH 7.4. MgCl and, whereappropriate, the other necessary cofactors for cytochrome P450 (CytP450)known from the literature were then added and the mixture was incubatedwith CytP450 3A4 (N-demethylation) and/or CytP450 2D6 (O-demethylation)at 37° C. The batch was subsequently separated via HPLC and themetabolites in the fractions were identified via NMR and then isolatedfrom the fractions.

Example 11 In Vivo Isolation of the Metabolites

A mammal was injected with[2-(3-methoxyphenyl)-cyclohexylmethyl]-dimethylamine hydrochloride andin a further example (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenolhydrochloride. Blood was taken from the mammal and, after separating offcorpuscular constituents, was separated via HPLC and the metabolites inthe fractions were identified via NMR and then isolated from thefractions.

Example 12 Parenteral Administration Form

1 g (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl) -phenol hydrochlorideis dissolved in 1 l water for injection purposes at room temperature andthe solution is then adjusted to isotonic conditions by addition ofNaCl.

Pharmacological Studies

a) Methods for Determination of the Affinity for the Human μ-OpiateReceptor and the 5-HT and NA Reuptake Inhibition

Investigation of the Affinity for the Human μ-Opiate Receptor

The receptor affinity for the human μ-opiate receptor is determined in ahomogeneous set-up in microtitre plates. For this, dilution series ofthe substances to be tested are incubated with a receptor membranepreparation (15-40 μg protein/250 μl incubation batch) of CHO-K1 cellswhich express the human μ-opiate receptor (RB-HOM receptor membranepreparation from Perkin Elmer, Zaventem, Belgium) in the presence of 1nmol/l of the radioactive ligand [³H]-naloxone (NET719, Perkin Elmer,Zaventem, Belgium) and 1 mg WGA-SPA-Beads (wheat germ agglutinin SPAbeads from Amersham/Pharmacia, Freiburg, Germany) in a total volume of250 μl for 90 minutes at room temperature. 50 mmol/l Tris-HClsupplemented with 0.05% sodium azide and with 0.06% bovine serum albuminis used as the incubation buffer. 25 μmol/l naloxone are additionallyadded for determination of the non-specific binding. After the end ofthe ninety-minute incubation time, the microtitre plates are centrifugedfor 20 minutes at 1,000 g and the radioactivity is measured in aβ-counter (Microbeta-Trilux, PerkinElmer Wallac, Freiburg, Germany). Thepercentage displacement of t h e radioactive ligand from its binding tothe human μ-opiate receptor is determined at a concentration of the testsubstances of 1 μmol/l and stated as the percentage inhibition of thespecific binding. Starting from the percentage displacement by variousconcentrations of the test substances, IC₅₀ inhibitory concentrationswhich cause a 50 per cent displacement of the radioactive ligand arecalculated. By conversion by means of the Cheng-Prusoff relationship,K_(i) values for the test substances are obtained (Cheng and Prusoff1973).

Investigations of the 5-HT and NA Reuptake Inhibition

In order to be able to carry out these in vitro studies, synaptosomesare freshly isolated from areas of the rat brain. In each case aso-called “P₂” fraction, which is prepared exactly in accordance withthe instructions of Gray and Whittaker (1962), is used. For the NAreuptake these vesicular particles are isolated from the hypothalamus,and for the 5-HT reuptake from the medulla+pons region of male ratbrains.

The following characteristic data were determined for the NA and 5-HTreuptake:

-   NA uptake: Km=0.32±0.11 μM-   5-HT uptake: Km=0.084±0.011 μM-   (In each case N=4, i.e. means ±SEM from 4 independent series of    experiments, which were carried out in triplicate parallel studies).

A detailed description of the method is contained in the publication ofFrink, Hennies, Englberger et al. (1996) (the study can also beconducted on microtitre plates (250 μl/well) at room temperature).

Evaluations:

In addition to % inhibitions at fixed test substance concentrations(e.g. 1×10⁻⁶ M or 1×10⁻⁵ M in the batch), dose dependencies wereinvestigated. IC₅₀ values are obtained by this means, and can beconverted into inhibitor constants (K_(i)) in accordance with the“Cheng-Prusoff equation” (Cheng and Prusoff 1973). The IC₅₀ values wereobtained with the aid of the computer program “Figure P” (version 6.0,Biosoft, Cambridge, England). Km values were calculated in accordancewith the method of Lineweaver and Burk (1934). The computer program“Ligand” (version 4, Biosoft, England) was used to display K_(D) values.

Literature:

Frink; M. Ch., Hennies, H.-H., Englberger, W., Haurand, M. and WilffertB. (1996) Arzneim.-Forsch./Drug Res. 46 (III), 11, 1029-1036

Gray, E. G. and Whittaker V. P. (1962) J. Anat. 76, 79-88

Cheng, Y. C. and Prusoff, W. H. (1973) Biochem. Pharmacol. 22, 3099-3108

Lineweaver, H. and Burk, D. (1934) J. Am. Chem. Soc. 56, 658-666

A clear affinity for the p-opiate receptor and an inhibition ofserotonin or noradrenaline reuptake were measured for the compoundsaccording to the invention. For the compound3-(2-dimethylaminomethyl-cyclohexyl)-phenol in particular a balancedratio between the μ-opioid component and the monoamine reuptakeinhibition was found, the latter being in the order of magnitude ofsubstances used clinically. The compound3-(2-dimethylaminomethyl-cyclohexyl)-phenol therefore has a verypromising potential for use as an anxiolytic, antidepressant andanalgesic.

The results of examples and for the reference substance venlafaxine areshown in the following table. TABLE 1 μ-Opioid receptor affinity 5-HTreuptake NA reuptake (Ki values inhibition (Ki inhibition (Ki Compound(μmol/l) values, μmol/l) values, μmol/l) 3-(2- 0.14 0.05 0.16Dimethylaminomethyl- cyclohexyl)-phenol, hydrochloride3-(2-Methylaminomethyl- 0.87 5.67 0.48 cyclohexyl)-phenol hydrochlorideVenlafaxine inactive 0.062 0.45

b) Investigation of the Onset of Anxiolytic Actions in the Elevated PlusMaze Test on Rats

In the elevated plus maze test the actions of substances on theendogenous anxiety of rodents towards open and elevated places aredetermined.

The apparatus was placed approx. 1 m above the floor and comprised fourarms arranged in a cross, two opposite arms being open and two closed.The rats were placed individually in the central square compartment,from where access to all four arms was possible, and the behaviour ofthe animals was observed for 5 minutes. The duration of stay and thenumber of entries into the open arms were evaluated. The group size was10-15 animals. The single administration of the test substances or ofthe control vehicle took place 30 min before testing.

It is reported in the literature that benzodiazepines induce anincreased duration of stay and entries into the open compartment. Incontrast, antidepressants of which the main mechanism is inhibition ofreuptake of the monoamines serotonin and/or noradrenaline cause noanxiolytic action, but in some cases anxiogenic effects, after a singleadministration in the elevated plus maze test, and anxiolytic effectscan be observed only after chronic administration over 2-4 weeks(Borsini, F., Podhorna, J., Marazziti, D., Psychopharmacology, 2002,163, p. 121-141). The typical disadvantages of monoamine reuptakeinhibitors in the therapy of anxiety patients, namely the delayed onsetof action and the initially anxiogenic-like effects, can thus befollowed in the elevated plus maze test on rats. The elevated plus mazetest is therefore a suitable animal model for the investigation of newtherapies which have the aim of accelerating the onset of action ofmonoamine reuptake inhibitors.

After a single administration of the compound3-(2-dimethylaminomethyl-cyclohexyl)-phenol, a significant increase inthe duration of stay and a clear increase in the number of entries intothe open arms and therefore significant anxiolytic actions weremeasured. In no case was an anxiogenic-like action induced after acuteadministration of the example of3-(2-dimethylaminomethyl-cyclohexyl)-phenol. When3-(2-dimethylaminomethyl-cyclohexyl)-phenol was combined with theμ-opiate receptor antagonist naloxone, the anxiolytic effects of3-(2-dimethylaminomethyl-cyclohexyl)-phenol could thereby be eliminatedcompletely. The naloxone sensitivity of the anxiolytic effects of3-(2-dimethylaminomethyl-cyclohexyl)-phenol demonstrate that the opiatecomponent of 3-(2-dimethylaminomethyl-cyclohexyl)-phenol is decisive forthe early onset of action after a single administration of thesubstance.

Diazepam caused an increase in the duration of stay and the entries intothe open arms. The mixed serotonin and noradrenaline reuptake inhibitorvenlafaxine showed no anxiolytic action after a single administration.

The results for 3-(2-dimethylaminomethyl-cyclohexyl)-phenol and for thereference substances diazepam and venlafaxine are shown in the followingtable. TABLE 2 Open arms Dose (mg/kg Duration of stay Number ofSubstance i.p.) (sec) entries Vehicle — 16.8 2.2 3-(2-Dimethylamino- 829.0 3.2 methyl-cyclohexyl)- 16 118.2* 8.5 phenol 3-(2-Dimethylamino-16 + 1 37.1# 1.6 methyl-cyclohexyl)- phenol + naloxone Naloxone 1 28.64.5 Diazepam 2 77.7* 8.1* Vehicle — 41.6 4.3 Venlafaxine 16 66.9 4.6

Statistical evaluation: Anova plus post-hoc Dunnett's test (Significancelevel: p<0.05; *: significant versus vehicle; #: significant versusintrinsic effect of 16 mg/kg i.p.3-(2-dimethylaminomethyl-cyclohexyl)-phenol).

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to person skilled in the art, theinvention should be construed broadly to include all variations withinthe scope of the appended claims and equivalents thereof.

1. A pharmaceutical formulation for treating anxiety disorders ordepression comprising a pharmaceutically effective amount of aC-(2-phenyl-cyclohexyl)-methylamine compound selected from the groupconsisting of 3-(2-dimethylaminomethyl-cyclohexyl)-phenol,(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol,[2-(3-methoxyphenyl)-cyclohexylmethyl]-dimethylamine,(1R,2R)-[2-(3-methoxyphenyl)-cyclohexylmethyl]-dimethylamine, sulfuricacid mono-[3-(2-dimethylaminomethyl-cyclohexyl)-phenyl] ester, sulfuricacid mono-(1R,2R)-[3-(2-dimethylaminomethyl-cyclohexyl)-phenyl] ester,3-(2-methylaminomethyl-cyclohexyl)-phenol,(1R,2R)-3-(2-methylaminomethyl-cyclohexyl)-phenol,3-(2-dimethylaminomethyl-cyclohexyl)-phenol, N-oxide, (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol, N-oxide,6-[3-(2-dimethylaminomethyl-cyclohexyl)-phenoxy]-3,4,5-trihydroxy-tetrahydropyran-2-carboxylicacid,6-[(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenoxy]-3,4,5-trihydroxy-tetrahydropyran-2-carboxylicacid, 4-(2-dimethylaminomethyl-cyclohexyl)-catechol,(1R,2R)-4-(2-dimethylaminomethyl-cyclohexyl)-catechol,3-(2-aminomethyl-cyclohexyl)-phenol,(1R,2R)-3-(2-aminomethyl-cyclohexyl)-phenol,C-[2-(3-methoxy-phenyl)-cyclohexyl]-methylamine,(1R,2R)-C-[2-(3-methoxy-phenyl)-cyclohexyl]-methylamine,[2-(3-methoxy-phenyl)-cyclohexylmethyl]-methylamine,(1R,2R)-[2-(3-methoxy-phenyl)-cyclohexylmethyl]-methylamine,[2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethylamine, N-oxide and(1R,2R)-[2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethylamine, N-oxide,or a physiologically acceptable salt thereof and a pharmaceuticallyacceptable carrier or adjuvant.
 2. The pharmaceutical formulation ofclaim 1, wherein said compound is present in the form of a free base. 3.The pharmaceutical formulation of claim 1, wherein said compound ispresent in the form of a pure enantiomer or pure diastereoisomer.
 4. Thepharmaceutical formulation of claim 1, wherein said compound is presentin the form of a mixture of stereoisomers.
 5. The pharmaceuticalformulation of claim 1, wherein said compound is present in the form ofa racemic mixture.
 6. The pharmaceutical formulation of claim 1, whereinsaid compound is present in the form of a solvate.
 7. The pharmaceuticalformulation of claim 1, wherein said compound is present in the form ofa hydrate.
 8. The pharmaceutical formulation of claim 1, wherein saidcompound is present in the form of a 1R,2R enantiomer.
 9. A method fortreating anxiety in a mammal, said method comprising administering to amammal in need thereof a pharmaceutically effective amount of apharmaceutical formulation according to claim
 1. 10. A method accordingto claim 9, wherein the pharmaceutical formulation is administered atthe first occurrence of an anxiety disorder.
 11. A method for treatinganxiety or depression in a mammal, said method comprising administeringto a mammal in need thereof a pharmaceutically effective amount of apharmaceutical formulation according to claim 1, saidC-(2-phenyl-cyclohexyl)-methylamine compound being administered as anadjuvant to at least one antidepressant.